Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core

Molecules. 2022 Dec 21;28(1):36. doi: 10.3390/molecules28010036.

Abstract

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

Keywords: Alzheimer’s disease; Down syndrome; antioxidant; dihydroquinoline; dual inhibitor; hCLK1; hDYRK1A; molecular docking; radical scavenger.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Down Syndrome / drug therapy
  • Dyrk Kinases
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Quinones* / chemistry
  • Quinones* / pharmacology
  • Quinones* / therapeutic use

Substances

  • Glycogen Synthase Kinase 3
  • Protein Kinase Inhibitors
  • Clk dual-specificity kinases
  • 1,4-dihydroquinone
  • Quinones

Grants and funding

This work was partially supported by the University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research Xl-Chem (ANR-18-EURE-0020 XL CHEM), and by Région Normandie.